The use of radiometal-labeled complexes and biomolecules as diagnostic agents is a relatively new area of medicinal chemistry. Research into 99mTc radiopharmaceutical was the beginning of the study of coordinate chemistry as it related to diagnostic imaging. Since then, the development of novel radiopharmaceuticals for early stage diagnosis remains as one of the active areas of functional imaging. In recent years, the imaging modalities widely used in nuclear medicine include gamma scintigraphy and positron emission tomography (PET). Gamma scintigraphy requires a radiopharmaceutical containing a nuclide that emits gamma radiation and a gamma camera or SPECT (single-photon emission tomography) camera capable of imaging the patient injected with a gamma-emitting radiopharmaceutical. The energy of the gamma photons is of great importance, since most gamma cameras are designed in the range of 100-250 KeV. Radionuclides that decay with gamma energies lower than this range produce too much scatter, while gamma energies >250 KeV are difficult to collimate, and in either case the images may not be of sufficient quality. PET requires a radiopharmaceutical labeled with a positron-emitting radionuclide (□+) and a PET camera for imaging the patient. Positron decay results in the emission of two 511 KeV photons 180° apart. PET scanners contain a circular array of detectors with coincidence circuits designed to specifically detect the 511 KeV photons emitted in opposite directions. Radiometal agents are also used to monitor various types of cancer therapy. In designing radiometal-based radiopharmaceuticals important factors to consider include the half-life of the radiometal, the mode of decay and the cost and the availability of the isotope. For diagnostic imaging, the half-life of the radionuclide must be long enough to carry out the desired chemistry to synthesize the radiopharmaceutical and long enough to allow accumulation in the target tissue in the patient while allowing clearance through the nontarget organs. Radiometals for radiopharmaceuticals used in PET and gamma scintigraphy range in half-life from about 10 min (62Cu) to several days (67Ga). The desired half-life is dependent upon the time required for the radiopharmaceutical to localize in the target tissue. For example, heart or brain perfusion-based radiopharmaceuticals require shorter half-lives, since they reach the target quickly whereas tumor-targeted compounds often take longer to reach the target for optimal target-to-background ratios to be obtained.
The design of a radiopharmaceutical agent requires optimizing the balance between specific in vivo targeting of the disease site (cancerous tumor) and clearance of radioactivity from non-target as well as the physical radioactive decay properties of the associated radionuclide. Several difficulties are encountered in the design of selective radiolabeled drug. These include problems related to efficient drug delivery, maximizing the residence time of the radioactivity at target sites, in vivo catabolism and metabolism of the drug, and optimization of relative rates if the radiolabeled drug or -metabolic clearance from non-target sites. Because of the multiple parameters that must be considered, developing effective radiopharmaceuticals for imaging and therapy of cancer is a complex problem that is not simply accomplished by attaching a radionuclide, in any fashion, to a non-radiolabled targeting vector. The chemistry involved in the labeling process, therefore, is an integral and essential part of the drug design process. For example, if a radiometalated chelate is appended at some point to a biomolecular targeting entity, the structure and physiochemical properties of the chelate must be compatible with, and possibly even help promote, high specific uptake of the radiopharmaceutical at the diseased site. At the very least, this radiometal chelate should not interfere with pharmacokinetics, binding specificity or affinity to cancer cells. Clearly, the selection of the radionuclides, and the chemical strategies used for radiolabeling of molecules are critical elements if the formulation of safe and effective imaging/therapeutic agents.
For the last several years porphyrin-based compounds have been used for the treatment of cancer by photodynamic therapy (PDT). The concentration of certain porphyrins and related tetrapyrrolic systems is higher in malignant tumors than in most normal tissues and that has been the main reason to use these molecules as photosensitizers. Some tetrapyrrole-based compounds have been effective in a wide variety of malignancies, including skin, lung, bladder, head and neck and esophagus. The precise mechanism(s) of PDT are unknown; however, the in vivo animal data suggest that both direct cell killing and loss of tumor vascular function play a significant role.
Photodynamic therapy (PDT) exploits the biological consequences of localized oxidative damage inflicted by photodynamic processes. These critical elements are required for initial photodynamic processes to occur: a photosensitizer, light and oxygen. Superficial visible lesions, or those that are endoscopically accessible, e.g. endobronchial or esophageal tumors, are easily treated but the majority of malignant lesions are too deep to be reached by light of the wavelength required to trigger singlet oxygen production in the current generation of photosensitizers. Although the technology to deliver therapeutic light to deep lesions via optical fibers “capped” by a terminal diffuser is well developed, a deep lesion is by definition not visible from the skin surface and the PDT of deep tumors has thus far been impractical.